Apolipoprotein AIV (apo AIV) is a circulating signal released from intestinal cells in response to lipid feeding, and it contributes to the anorectic effect of a lipid meal. We have demonstrated that apo AIV is also synthesized in the hypothalamus, and that hypothalamic apo AIV gene expression is regulated physiologically. Our long-range goal is to understand the role of hypothalamic apo AIV in the development of obesity and how it can be modulated for preventive and therapeutic purposes. The objective of this application is to evaluate three hypotheses. 1) When hypothalamic apo AIV function is reduced, meal size is chronically increased and obesity develops. Obese animals will, therefore, have lower hypothalamic apo AIV levels and/or lower responsivity of hypothalamic apo AIV to dietary lipids relative to lean animals. 2) Peripheral apo AIV contributes to the central action of apo AIV after crossing the blood-brain barrier (BBB). Therefore, impaired transport across the BBB may result in reduced hypothalamic apo AIV levels and action in obese animals. 3) Hypothalamic apo AIV interacts with other regulatory neuropeptides to exert its physiological function. These hypotheses will be evaluated with the following three specific aims: 1) To determine hypothalamic apo AIV gene expression and protein levels and the responsivity of hypothalamic apo AIV to dietary lipids in several strains of obese and lean animals. We will further determine the response to chronic high-fat feeding in apo AIV knockout mice. 2) To characterize the transport of apo AIV from blood into the central nervous system (CNS) and to assess the areas in the brain that are activated by apo AIV administered either centrally or intravenously. 3) To determine the interaction of apo AIV with other regulatory peptides within the hypothalamus. The proposed work is innovative because it addresses important unanswered questions. In addition, the proposed research takes advantage of the availability of experimental methods and several unique animal models. Finally, the outcomes of the research will be significant because it is expected that these studies will contribute to broader understanding of the role of apo AIV in the regulation of energy homeostasis. This new knowledge may lead to novel targets for preventive and therapeutic interventions that will be particularly important to the growing numbers of obese persons in this country.